2. Flavonols

Structure of Flavonols

Flavonols are a major class of the family of flavonoids. Flavonoids are 2 phenyl benzo-γ-pyrone derivatives. A common part in the chemical structure of all flavonoids is a 15-carbon skeleton based on a flavan structure (C6-C3-C6) consisting of two aromatic rings (A and B) linked by a heterocyclic pyrane or pyrone ring (C). A wide diversity of flavonoids stems from the fact that carbon atoms of A, B and C rings may undergo hydroxylation, methoxylation and glycosidation by means of mono- and oligosaccharides, as well as acylation at different positions. Biogenesis of flavonoids is a complex process. They are created from precursors of primary metabolism during a transformation creating two pathways, as shown in Figure 1. The first one is a malonic acid pathway, in which malonyl coenzyme A is created from acetyl coenzyme A produced through glycolysis; three molecules of malonyl-CoA obtained from glucose transformation are the source of the aromatic ring A. The second one is a shikimic acid pathway, in which erythrose-4-phosphate derived from the pentose phosphate pathway and phosphoenolpyruvate created via glycolysis are transformed into shikimic acid, and then, into aromatic amino acids: phenylalanine and tyrosine. During subsequent transformations, both amino acids undergo deamination, and consequently, form cinnamic acid. Condensation of ring A and ring B results in creation of chalcone, which undergoes cyclization with isomerase, and a flavanone is produced—a starting compound for synthesis of the remaining groups of flavonoids ^[2][3][3,4].

Figure 1. Biosynthesis pathway of phenylpropanoids and flavonols. Biosynthesis of flavonols from p-coumaroyl-CoA and malonyl-CoA. Enzymatic reaction catalyzed by DAHPS: 3-deoxy-D-arabino-heptulosonate-7-phosphate-synthase; DHQS: 3-dexydroquinate synthase; SDO: shikimate dehydrogenase; PAL: phenylalanine ammonia-lyase; TAL: tyrosine ammonia lyase; C4H: cinnamate 4-hydroxylase; CHI: chalcone isomerase, FHT: flavanone 3β-hydroxylase; FNS Ι: flavone synthase Ι; FLS: flavonol synthase; FMO: flavonoid 3′-monooxygenase; CPR: cytochrome P450reductase ^[4][5][6][8,9,10].

All naturally found flavonoids have three hydroxyl groups: two found in ring A at position 5 and 7, and one in ring B at position 3. Diverse positions of substituents in a flavonoid molecule give it different chemical and physical properties, which translates into an individual metabolism of a given compound and its biological activity. Flavonoids, except for isoflavones, have their aromatic ring attached to pyrone C2, whereas in isoflavones it is attached to C3 ^{[2][3][7][8][9]}[3,4,5,6,7].

Chemically, flavonols differ from many other flavonoids, because they have a double bond between position 2 and position 3 as well as oxygen (a ketone group) at position 4 of ring C similarly to flavones, from which they yet differ due to the presence of hydroxyl group at position 3 (FigureFigure 2 2 and Figure 3).

Figure 2. Basic skeleton or structure of flavonols.

Figure 3. Structures of selected flavonols.

Thus, flavonol’s skeleton is 3-hydroxyflavone. 3′ hydroxyl group may attach sugar, i.e., it might be glycosylated. It was shown that three structural groups are important for biological activity, including anti-oxidative and radical-scavenging activity of flavonoids: (1) o-dihydroxyl group in ring B; (2) double bond at 2,3 attached to 4-oxy group in ring C; and (3) hydroxyl groups at positions C3 and C5. Moreover, a 3′,4′-o-dihydroxyl group is an indicator of a considerable antioxidant activity of flavonoids, especially those that do not belong to the flavonol subclass. Ring B catechol group is critical for high antioxidant activity. A higher antioxidant activity of flavonoids with o-dihydroxyl group in ring B is attributed to their greater radical stability via an increased delocalization of electrons and intramolecular hydrogen bonds between 3′- and 4′-hydroxyl groups. Additionally, 5′-hydroxyl group in ring B, as seen in myricetin and azaleatin, decreases the antioxidant activity, which might be caused by a prooxidant activity introduced by a pyrogallol group. ^[10][11][12][11,12,13].